Mulcahy, B., Waldron-Lynch, F., McDermott, M.F., Adams, C., Amos, C.I., Zhu, D.K.,Ward, R.H., Clegg, D.O., Shanahan, F., Molloy, M.G., and O'Gara, F.;

1996

September

American Journal of Human Genetics

Genetic variability in the tumor necrosis factor-lymphotoxin region influences susceptibility to rheumatoid arthritis.

Published

()

SHARED-EPITOPE HYPOTHESIS MAJOR HISTOCOMPATIBILITY COMPLEX DEPENDENT DIABETES-MELLITUS FACTOR-ALPHA CEREBRAL MALARIA HLA COMPONENT TNF-ALPHA ASSOCIATION LOCUS BETA

59

3

676

683

The major histocompatibility complex class III tumor necrosis factor-lymphotoxin (TNF-LT) region (6p21.3) was investigated as a possible susceptibility locus for rheumatoid arthritis (RA). Inheritance of five TNF microsatellite markers was determined in 50 multiplex families. Overall, 47 different haplotypes were observed. One of these, the TNF a6, b5, cl, d3, e3 (H1) haplotype, was present in 35.3% of affected, but in only 20.5% of unaffected, individuals (P < .005). This haplotype accounted for 21.5% of the parental haplotypes transmitted to affected offspring and only 7.3% not transmitted to affected offspring (P = .0003). The TNF a6 and TNF cl alleles were individually associated with RA (P = .0005 and .0008, respectively), as were the HLA-DRB1 ''shared epitope'' (SE) (P = .0001) and HLA-DRB1*0401 (P = .0018). Both univariate and bivariate conditional logistic regression analysis showed significant effects of TNF cl and SE in increasing risk to RA (P < .001). Stratification by the presence of SE indicated an independent effect of the TNFc1 allele (P = .0003) and the HLA A1, B8, DR3 extended haplotype (always TNFa2, b3, cl, dl, e3) (P = .0027) in SE heterozygotes, while the H1 haplotype was associated with RA in SE homozygotes (P = .0018). The TNF-LT region appears to influence susceptibility to RA, distinct from HLA-DR.